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Diabetic Foot

By Scott Bergman, Pharm.D., BCPS-AQ ID; and Punit J. Shah, Pharm.D., BCPS

Reviewed by Douglas N. Fish, Pharm.D., FCCP, BCPS-AQ ID; Sonal Taylor, Pharm.D., BCACP; and Mary J. Thoennes, RPh, BCACP, NCPS

LEARNING OBJECTIVES

1. Distinguish the factors that increase the risk of diabetic foot infections (DFIs) in a patient. 2. Assess the severity and extent of DFI on the basis of clinical tests and findings. 3. Evaluate a patient’s risk factors for multidrug-resistant organisms when selecting an appropriate empiric antimicrobial therapy for DFIs. 4. Analyze differences between therapeutic agents in and efficacy depending on the severity and extent of DFI. 5. Design an appropriate antimicrobial treatment and monitoring plan for a patient with a DFI with or without . 6. Develop a plan to prevent diabetic foot ulcers in the patient with .

INTRODUCTION ABBREVIATIONS IN THIS CHAPTER According to the CDC, the number of Americans with a diagnosis of DFI Diabetic foot diabetes more than tripled between 1980 and 2012 (from 5.5 million DFO Diabetic foot osteomyelitis to 21.3 million) (CDC 2014). This number continues to rise, and with DFU it, the number of patients at risk of microvascular and macrovascular HBOT Hyperbaric oxygen therapy complications. Foot problems are common in patients with diabe- MRSA -resistant tes. Complications related to foot diseases in patients with diabetes aureus include Charcot arthropathy, foot ulceration, infection, osteomyelitis, MSSA Methicillin-sensitive and limb . However, the development of a diabetic foot ulcer (DFU) and subsequent infection is preventable. Pharmacists SSTI Skin and soft tissue infection play a vital role by monitoring, educating, and empowering patients. Table of other common abbreviations. This chapter focuses on the treatment of diabetic foot infections (DFIs), including osteomyelitis, in the primary care setting.

Epidemiology and Impact Among patients with diabetes, diseases of the feet are more com- mon in men and in individuals older than 60 years. In their lifetime, about 25% of patients with diabetes will have a significant skin and soft tissue infection (SSTI) because of predisposing vascular insuf- ficiency, neuropathy, and impaired immunity. The most common foot infections are DFIs, and these patients have higher recurrence and hospitalization rates (Lipsky 2012). Diabetic foot infections decrease quality of life and increase morbidity, physical and emotional dis- tress, and health care costs. The number of hospital discharges for patients with diabetes and peripheral arterial disease, ulcer/inflam- mation/infection, and neuropathy doubled from 445,000 in 1988 to 890,000 in 2007 (CDC 2014).

ACSAP 2016 Book 3 • Infection Primary Care 7 Diabetic Foot Infections Diabetic foot infections can spread contiguously to deeper muscle, difficulty walking and standing, loss of reflexes, and tissues, including bone. If the infection progresses, it may foot deformities, among other problems. Therefore, regular eventually be necessary to amputate the limb. The mean foot care is essential to prevent foot ulcers and associated hospital charge for one episode of foot or toe osteomyelitis morbidity and mortality in patients with diabetes. A compre- is around $19,000. In addition, in 1988–2009, hospital dis- hensive yearly foot examination is recommended; patients charges for nontraumatic lower-extremity amputation in with a history of ulcers, , foot deformities, periph- patients with diabetes increased by 24% (CDC 2014). eral neuropathy, and peripheral arterial disease should have their feet examined at every visit. PATHOGENESIS Other risk factors for foot ulcers and infection include poor control, which impairs immunologic function, espe- Risk Factors for DFUs and Infection cially action of polymorphonuclear (PMN) leukocytes, humoral Foot ulcers and infection usually occur after trauma. Several immunity, and cell-mediated immunity. In addition, patients factors predispose a patient with diabetes to foot ulcers and with diabetes may have decreased local and systemic inflam- infections. Patients with diabetes often have peripheral sen- matory responses to infection and poor wound healing because sory and motor neuropathy: increases of peripheral arterial disease in the affected limb. Peripheral the risk of foot ulcers by 7-fold (Khanolkar 2008). Patients arterial disease is present in 20%–30% of patients with diabetes with diabetes lose the protective sensations for tempera- and in up to 40% of those with DFI; it is also the most important ture and and are often unaware of trauma to their feet. predictor for recovery after DFI (Schaper 2012). A multivariate Furthermore, motor neuropathy leads to wasting away of analysis showed that the risk factors most associated with developing foot infections were wounds that penetrated to the bone (OR 6.7), lasted more than 30 days (OR 4.7), were recurrent (OR 2.4), that had a traumatic etiology (OR 2.4), or that occurred BASELINE KNOWLEDGE STATEMENTS in patients with peripheral vascular disease (OR 1.9) (Lavery Readers of this chapter are presumed to be familiar 2006). Box 1-1 lists the risk factors for DFIs. with the following: • General knowledge of the pathophysiology that Complications leads to diabetic foot ulcers and infection in Breaks in skin expose underlying tissues to colonization by patients with diabetes pathogenic organisms including multidrug-resistant organ- • of activity and pharmacokinetics of isms such as methicillin-resistant Staphylococcus aureus antimicrobials (MRSA). The resulting infection may begin superficially, but • Diabetes care standards with a delay in treatment and the impaired body defense mechanisms caused by neutrophil dysfunction and vascular Table of common laboratory reference values. insufficiency, it can spread to the contiguous subcutane- ous tissues and deeper structures (e.g., bone). Diabetic foot

ADDITIONAL READINGS osteomyelitis (DFO) is present in up to 20% of mild-moder- ate DFIs and 50%–60% of severely infected wounds. Diabetic The following free resources have additional back- foot osteomyelitis increases the likelihood of surgical inter- ground information on this topic: vention, including amputation. • Infectious Diseases Society of America. Clinical Patients with DFIs may also present with signs of systemic practice guideline for the diagnosis and treatment inflammatory response syndrome, as manifested by at least of diabetic foot infections. Clin Infect Dis 2012;54:132-73. • Liu C, Bayer A, Cosgrove SE, et al. Practice guidelines by the Infectious Diseases Society of Box 1-1. Risk Factors for Diabetic Foot America for the treatment of methicillin-resistant Infections Staphylococcus aureus infections in adults and Presence of peripheral vascular disease in the affected children. Clin Infect Dis 2011;52:1-38. • limb • Stevens DL, Bisno AL, Chambers HF, et al. Practice • Poor glycemic control guidelines for the diagnosis and management of • Loss of protective sensation (i.e., neuropathy) skin and soft tissue infections: 2014 update by the • Traumatic foot wound Infectious Diseases Society of America. Clin Infect • Ulceration > 30 days Dis 2014;59:e10-59. • History of recurrent foot ulcers • American Diabetes Association (ADA). Standards • Previous lower-extremity amputation of Medical Care in Diabetes – 2016. Diabetes Care • Improper footwear 2016;39:S1-S112. • Wounds that penetrated to bone

ACSAP 2016 Book 3 • Infection Primary Care 8 Diabetic Foot Infections two of the following: WBC greater than 12 × 103 cells/mm3 or Classification of Infection less than 4 × 103 cells/mm3 or 10% bands or more; respira- There are several published classification schemes and wound scoring systems; however, none is considered to be a tory rate greater than 20 breaths/minute or Paco2 less than 32 mm Hg; temperature greater than 38°C or less than 36°C; and gold standard. Examples of classification schemes are those heart rate greater than 90 beats/minute. from the International Working Group on the Diabetic Foot (IWGDF) and the Infectious Diseases Society of America (IDSA). The IWGDF classifies diabetic foot wounds using the ASSESSMENT acronym PEDIS (perfusion, extent, depth, infection, sensa- Is It Infected? tion). The PEDIS grades for DFI are 1–4, with the lowest grade Not all DFUs are infected. Therefore, DFIs must be diagnosed for no symptoms or signs of infection and the highest grade clinically, rather than only reviewing wound culture results, for presence of local and systemic signs and symptoms of because microorganisms can colonize all wounds. Local infection. The IDSA classifies the infection as uninfected, signs and symptoms of infection include swelling, warmth, mild, moderate, or severe. Grading or classification is tenderness, pain, erythema, and purulent secretions. Patients based on local and systemic manifestations, and extent of with may be unable to describe pain infection. Table 1-1 summarizes the IWGDF and IDSA classi- at the infection site. In addition, patients with limb ischemia fication systems. secondary to peripheral vascular disease may not have ery- thema, warmth, or swelling around the infected ulcer. In these Microbiology patients, it may be appropriate to seek secondary signs of For uninfected wounds, specimen collection for culture is infection, such as abnormal coloration around the wound, a not recommended because it will likely yield only skin flora fetid odor from the infected ulcer, friable granulation tissue, and microorganisms and lead to unnecessary antimicrobial and undermining of the wound edges. therapy. For patients who have not been treated with antibi- Systemic signs and symptoms of infection may be absent otics in the past 30 days and have a mild DFI, infections are in up to 50% of patients. Presence of systemic signs and often monomicrobial. The most common causative organ- symptoms suggests severe infection with extensive tissue isms are aerobic gram-positive present on the skin involvement or a more virulent . Systemic signs and surface such as β-hemolytic streptococci ( symptoms include fever, chills, delirium, diaphoresis, anorexia, pyogenes, ) or S. aureus. In contrast, hemodynamic instability, and metabolic derangements (e.g., infections are usually polymicrobial in patients with diabetes acidosis, azotemia, electrolyte abnormalities). Patients may who have used in the past 30 days and in those also have leukocytosis and elevated nonspecific inflamma- with deep, limb-threatening infections or chronic non-healing tory markers such as C-reactive (CRP) and erythrocyte wounds. Anaerobic bacteria are generally part of polymicro- sedimentation rate (ESR). These inflammatory markers can bial infections in wounds with malodorous discharge, limb be tracked and may help determine when a DFI has resolved, ischemia, or gangrene. In one study, most patients with mod- allowing discontinuation of therapy. erate to severe DFIs had polymicrobial infections (83.8% of

Table 1-1. Classification of DFI: PEDIS and IDSA

Clinical Manifestation of Infection PEDIS Grade IDSA Infection Severity

No symptoms or signs of infection 1 Uninfected

Local infection (only skin and subcutaneous tissue). If erythema, 2 Mild must be > 0.5 cm to ≤ 2 cm around the ulcer

Local infection with erythema > 2 cm, or infection involving deeper 3 Moderate tissues (e.g., , osteomyelitis, , fasciitis) and < 2 signs of the systemic inflammatory response syndrome (SIRS)

Local infection with ≥ 2 signs of SIRS: Temperature > 38°C or < 36°C, 4 Severe

HR > 90 beats/min, RR > 20 breaths/min or Paco2 < 32 mm Hg and WBC > 12 x 103 cells/mm3 or < 4 x 103 cells/mm3 or ≥ 10% bands

HR = heart rate; RR = respiratory rate. Information from: Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:132-73.

ACSAP 2016 Book 3 • Infection Primary Care 9 Diabetic Foot Infections 427 cultures). Cultures yielded 1145 aerobic strains and 462 anaerobic strains, with an average of 2.7 aerobic organisms Box 1-3. Risk Factors for P. aeruginosa per culture (range 1–8) and 2.3 anaerobic organisms per cul- • Warm climate Frequent exposure of the foot to water (soaking feet) ture (range 1–9) (Citron 2007). • • Treatment failure with antibiotic therapy that has no In infected wounds, it is crucial to obtain appropriate cul- activity against P. aeruginosa tures to guide antibiotic therapy. Deep-tissue specimens • High local prevalence of P. aeruginosa (> 10% of dia- obtained after wound cleansing and debridement will yield betic foot wounds) true more reliably than specimens from superfi- • Severe diabetic foot infection cial wound swabs, which are often contaminated with normal Information from: Lipsky BA, Berendt AR, Cornia PB, et al. 2012 skin flora and colonizers. Less virulent bacteria such as Infectious Diseases Society of America clinical practice guide- -negative staphylococci, sp., and line for the diagnosis and treatment of diabetic foot infections. corynebacteria may not be true pathogens (Lipsky 2004). Clin Infect Dis 2012;54:132-73. The analysis of WBCs at the site of culture is very important. When reported with a Gram stain, the presence of PMN WBCs in a wound culture is predictive of infection rather than col- if at least 50% of all S. aureus isolates in the local area are onization. Anaerobic bacteria will not grow well in cultures methicillin resistant, empiric activity against MRSA is indi- taken from open wound cultures; hence, a Gram stain may cated for mild infection. For moderate DFIs, antibiotics with be the only indication of these organisms. Treatment with empiric activity against MRSA are recommended when the antimicrobials before culture will also decrease the growth local prevalence for MRSA is 30% or more. However, for all of bacteria in the laboratory. The Gram stain does not typi- severe DFIs, empiric activity against MRSA is recommended cally have this limitation because it can detect recently dead (Lipsky 2012; Moran 2006). and dying organisms. Therefore, Gram stain results should be considered when developing a treatment plan. P. aeruginosa Studies of complicated SSTI and DFI show that P. aeruginosa Risk Factors is isolated in less than 10% of wounds (in studies primar- Isolation of drug-resistant organisms such as MRSA ily from developed northern countries) (Noel 2008; Lipsky and aeruginosa from DFI is on the rise. 2005). Even though it is a virulent organism, these bacteria Understanding a patient’s risk factors for these two organ- are often a nonpathogenic colonizer of the feet, and patients isms will help in selecting an optimal empiric regimen for can improve, even with therapy ineffective against P. aerugi- patients who present with DFIs. nosa, if proper debridement and wound care are performed. In a study comparing / with Methicillin-Resistant S. aureus in patients with isolates of P. aeruginosa, clinical response Risk factors for MRSA infections (Box 1-2) necessitate its rates in DFIs were similar in both groups (70% vs. 83.3%, empiric treatment; these include a history of MRSA infec- respectively; 95% CI, -18.2 to 48.7), even though ertapenem tion or colonization within the past year, use of antibiotics in has no activity against the organism (Lipsky 2005). Risk fac- the past month, hospitalization in the past year, presence of tors for DFIs caused by P. aeruginosa are listed in Box 1-3). osteomyelitis, prison incarceration, close contact with a per- For all severe DFIs, empiric activity against P. aeruginosa is son with a similar infection, purulent drainage, and high local recommended. prevalence of MRSA colonization and infection. For example, TREATMENT For clinically uninfected wounds, no antimicrobial therapy is Box 1-2. Risk Factors for MRSA required. Unnecessary use of antibiotics leads to antibiotic • History of MRSA infection or colonization within the resistance, difficile , financial burden, and past year preventable adverse events. However, all infected wounds • Receipt of antibiotics in the past month should be treated with antimicrobial therapy and appropriate Hospitalization in the past year • wound care. Empiric antimicrobial therapy for DFIs should be • Presence of osteomyelitis • Prison inmates based on the severity of the infection and the likely causative • Close contact with a person who has a similar infection pathogen. Regardless of the antimicrobial, the best predictor of • Purulent drainage successful treatment is proper wound care, including drainage. • High local prevalence of MRSA (≥ 50% for mild infec- For patients with mild to moderate DFIs and no history of tions, ≥ 30% for moderate infections) recent antibiotic use (i.e., in the past 30 days), empiric anti- Severe diabetic foot infection • biotic therapy should target gram-positive cocci present on MRSA = methicillin-resistant Staphylococcus aureus. the skin, S. pyogenes (group A Streptococcus) and methicillin- sensitive S. aureus (MSSA). For mild to moderate DFIs with

ACSAP 2016 Book 3 • Infection Primary Care 10 Diabetic Foot Infections an abscess or purulence, or if the patient has risk factors for the first-line intravenous anti-MRSA agent. Antipseudomonal MRSA (see Box 1-2), antimicrobial therapy targeting MRSA agents (piperacillin/tazobactam, , , imi- and group A Streptococcus should be used. For patients with , , ) should only be used when P. mild to moderate DFIs and antibiotic use within the past 30 aeruginosa is suspected and the infection is life or limb threat- days, empiric antimicrobial therapy should also target gram- ening. Even then, immediate de-escalation should occur once negative . Empiric therapy directed at P. aeruginosa is the results of cultures and susceptibility testing are available. usually unnecessary except for patients with risk factors for are the drugs of choice for treating infections this organism (see Box 1-3). caused by that produce extended-spec- For severe DFIs, broad-spectrum antimicrobial therapy trum β-lactamases. These agents may be initiated empirically targeting gram-positive cocci, gram-negative bacilli, and obli- in patients with a history of infections caused by extended- gate anaerobes is recommended, including activity against spectrum β-lactamase–producing Enterobacteriaceae. MRSA and P. aeruginosa. Antimicrobial therapy should then be Consulting local antibiograms may be important because tailored to the results of an appropriately obtained Gram stain an increasing number of Enterobacteriaceae are resistant to and culture plus the patient’s clinical response. For mild and /clavulanate, /, ciprofloxacin, many moderate DFIs, oral antibiotics can be used in patients levofloxacin, and trimethoprim/sulfamethoxazole. for whom an antimicrobial with the appropriate spectrum is Although many antimicrobials are used clinically to treat available. For some moderate DFIs and for severe DFIs that soft tissue infections, only three have FDA-approved labeling require parenteral therapy initially, oral therapy can be used for DFIs: piperacillin/tazobactam, , and ertapenem. sequentially as a step-down once the patient is stable and In 2010, the FDA issued guidance for developing systemic infection is not progressing. Table 1-2 lists suggested empiric drugs to treat acute bacterial skin and skin structure infec- antimicrobial regimens for mild, moderate, and severe DFIs. tions. Infections needing more complex treatment regimens, Empirically, every effort must be made to preserve the including DFIs, were excluded. Hence, few new data have use of broader-spectrum and costlier antimicrobials. Newer, been published in this area. expensive anti-MRSA agents (e.g., ceftaroline, , Ceftaroline is an advanced-generation with linezolid, tedizolid, , , , tige- activity against MRSA as well as other gram-positive skin cycline) provide no additional benefit in efficacy outcomes pathogens. It was approved for treatment of skin and skin over , because studies of skin and skin struc- structure infections in 2011, although not indicated for dia- ture infection have not proved them superior to vancomycin. betic foot infections. Ceftaroline has activity against some Although these newer agents can be used because of vanco- gram-negative organism but is not effective against most mycin intolerance or failure, vancomycin is still preferred as anaerobes.

Table 1-2. DFI Microbiology and Recommended Empiric Antibiotic Therapy According to Severity

Severity Pathogensa Drugs

Mild-moderate Streptococcus sp., and MSSA • , cephalexin, , or amoxicillin/ • Outpatient management MRSA (for risk factors, see Box 1-2) clavulanate • Treated with oral agents • Clindamycin, doxycycline, minocycline, trimethoprim/sulfamethoxazole, or linezolid

Moderate MRSA, gram-negative bacilli, • Vancomycin + ampicillin/sulbactam, moxifloxacin, • Hospitalization warranted anaerobes , or • May be treated initially with • Vancomycin + + , parenteral agents ciprofloxacin, or levofloxacin

Severe MRSA, gram-negative bacilli including • Vancomycin + piperacillin/tazobactam, / • ICU admission P. aeruginosa, anaerobes cilastatin, meropenem, or doripenem • Life or limb threatening • Vancomycin + metronidazole + ceftazidime, cefepime, ciprofloxacin, or levofloxacin

aTreat for MRSA in patients with risk factors as described in Box 1-2; treat for P. aeruginosa in patients with risk factors as described in Box 1-3.

Information from: Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:132-73.

ACSAP 2016 Book 3 • Infection Primary Care 11 Diabetic Foot Infections In 2014, three new antimicrobials were approved for the osteomyelitis existed at the time of study entry (Corey 2015). treatment of skin and skin structure infections: tedizolid, ori- Oritavancin can artificially prolong coagulation tests, including tavancin, and dalbavancin. However, data are limited on the activated clotting time, prothrombin time, and INR. This can be use of these agents in DFIs and osteomyelitis. Tedizolid is a concern in the ambulatory patient population taking warfarin, an oxazolidinone, similar to linezolid, but can be dosed once- which may not be monitored closely. The average wholesale daily instead of twice. It might be less likely to interact with price of the is around $3000 per initial dose. serotonergic agents, although human clinical data on this Favorable bone concentrations of dalbavancin above the MIC are lacking. Tedizolid also may cause less thrombocytopenia for common gram-positive pathogens that cause bone and than linezolid, but trials with the drug for acute bacterial skin joint infections have been observed in rabbits (Solon 2007). In and skin structure infections focused on a short treatment addition, results were recently replicated in human volunteers course (6 vs. 10 days), and this is more likely to undergoing knee and hip arthroplasties (Dunne 2015). occur after 2–3 weeks of therapy with linezolid. A coordinated and multidisciplinary team approach is rec- Oritavancin and dalbavancin are both long-acting lipoglyco- ommended for managing DFIs. This team should include peptides with mechanisms of action similar to those of both infectious diseases physicians for treatment recommenda- vancomycin and telavancin. The half-lives of these drugs are tions and management of appropriate antibiotic therapy, over 240 hours with very little removal by dialysis, should an microbiologists for accurate identification of organisms, a adverse event occur. Of patients receiving oritavancin in clin- general surgeon for appropriate debridement and drainage, ical trials, 14% had diabetes. The prescribing information vascular surgeons if the limb is ischemic, nurses, podiatrists, carries a warning not to use the drug in patients with sus- wound care specialists, and pharmacists for pected osteomyelitis; this is because osteomyelitis developed supervision and counseling, as well as diabetes education more often in patients treated with oritavancin than in those and management. treated with vancomycin. At the end of the SOLO II trial, five patients in the oritavancin group had osteomyelitis versus Topical Therapy none in the vancomycin arm. Osteomyelitis occurred within Several topical antibiotic preparations are available, includ- 1–9 days of oritavancin administration, which suggests that ing some OTC products, which may be suitable for use in

Patient Care Scenario A 72-year-old man (weight 91 kg) presents with a 3-day vascular disease, and a 15-month history of a diabetic history of right foot swelling, erythema, and pain, with a right foot ulcer. The patient has no antibiotic . yellow foul-smelling purulent discharge from a foot ulcer. The patient has no systemic signs of infection, and the The erythema is 3 cm around the ulcer. His medical his- physician asks you to develop an antimicrobial regimen tory is significant for (A1C 1 week ago was for this patient. 9.5%), , peripheral neuropathy, peripheral • What are the patient’s risk factors for DFI? • How would you classify this patient’s infection? • What would be this patient’s empiric antimicrobial regimen? ANSWER This patient has several risk factors for DFI, including a susceptibilities. For moderate infection, oral or intrave- chronic foot ulcer (greater than 30 days), uncontrolled dia- nous antimicrobials can be used (see Table 1-2). Because betes (A1C 9.5%), peripheral neuropathy, and peripheral the patient has purulent discharge, MRSA should be tar- vascular disease. According to the IWGDF classification, geted with empiric therapy. Other organisms that should he would be assigned a PEDIS grade 3, and according be covered include group A streptococci, gram-negative to the IDSA classification, he has a moderate DFI. This bacilli (e.g., Enterobacteriaceae but not P. aeruginosa), is because the patient has no systemic manifestations, and anaerobes. All antibiotic options for the treatment of but local signs and symptoms of infection for the patient moderate DFI listed in Table 1-2 are reasonable: vancomy- include swelling, erythema, pain, and yellow foul-smelling cin plus ampicillin/sulbactam, moxifloxacin, cefoxitin, or purulent discharge from ulcer. In addition, the erythema cefotetan; or vancomycin plus metronidazole plus ceftri- around the ulcer is 3 cm. axone, ciprofloxacin, or levofloxacin. Local antibiograms should be consulted because of the increasing resis- The patient should have any underlying abscess tance to fluoroquinolones and ampicillin/sulbactam seen drained and cultured to identify the organism(s) and among those with Enterobacteriaceae.

1. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:132-73. 2. Bader MS. Diabetic foot infection. Am Fam Physician 2008;78:71-9.

ACSAP 2016 Book 3 • Infection Primary Care 12 Diabetic Foot Infections treating mild DFI. Examples are mupirocin, retapamulin, tri- because of GI intolerance at higher doses. This is important ple antibiotic cream/ointment (which contains , because of the high rate of peripheral vascular disease in neomycin, and B), and double antibiotic cream/ patients with diabetes and the limited amount of drug that ointment (which contains bacitracin and ). Other can reach the infection site. Other antibiotics with excel- topical antibiotic preparations such as topical clindamycin, lent that have equivalent intravenous-to-oral , benzoyl peroxide, sulfacetamide, and dap- conversions (1:1, unless noted) include levofloxacin, moxiflox- sone are limited to the treatment of Propionibacterium acnes, acin, ciprofloxacin (0.8:1), trimethoprim/sulfamethoxazole, which is not a likely pathogen of the feet. Topical linezolid, tedizolid, doxycycline, minocycline, and metronida- and antiviral preparations are also available, but they have a zole. Although 90% of oral clindamycin is absorbed, doses negligible role in DFIs. greater than 600 mg orally every 8 hours are generally not Topical treatment avoids systemic adverse events, pro- well tolerated because they lead to GI adverse effects. vides drug therapy at the site of action, and allows the use For patients with risk factors for MRSA, linezolid has the of agents not available for systemic therapy or too toxic for most evidence and has been proved at least as effective as routine use in DFI (e.g., polymyxin B). However, topical ther- vancomycin. Linezolid has very high tissue penetration, even apy should only be used for mild, superficial, and small DFIs. with the oral formulation. Generic linezolid is now available Limited and conflicting data exist for using topical antimicro- commercially. However, it is still more expensive than older bial therapy for mild DFIs. In two consecutive double-blind, drugs, and patient assistance programs will no longer be controlled trials (study 303 and 304), patients with mild DFIs available. were randomized to receive either topical pexiganan or oral Historically, trimethoprim/sulfamethoxazole has been ofloxacin. Topical pexiganan is a broad-spectrum peptide used as an alternative for minor infections, but it is consid- antimicrobial with activity against a wide range of gram-pos- ered less effective than vancomycin for serious infections. itive and gram-negative aerobic and anaerobic bacteria, Trimethoprim/sulfamethoxazole also has questionable activ- including S. aureus and P. aeruginosa. The primary outcome ity against group A streptococci, as evidenced by its higher of these two trials was clinical cure or improvement of the failure rates for streptococcal pharyngitis than β-lactams. infection. For study 303, the pexiganan arm failed to show This has led some experts to recommend combination ther- equivalence in clinical cure or improvement to the oflox- apy with trimethoprim/sulfamethoxazole plus a β-lactam for acin arm (85% vs. 91.1%; 95% CI, -11.74 to -0.33). Study 304, treatment of skin infections when the etiology is unknown. however, showed the pexiganan arm to be equivalent to the Doxycycline is another orally available option for the treat- ofloxacin arm in clinical cure or improvement (89.5% for both ment of minor MRSA skin infections. It has concerns similar treatment arms; 95% CI, -6.51 to 6.51) (Lipsky 2008). to trimethoprim/sulfamethoxazole regarding efficacy against Topical therapy does not attain deep tissue penetration β-hemolytic streptococci. or systemic therapeutic concentrations; as a result, topical Clindamycin has better streptococcal activity, but resis- antimicrobial therapy for DFIs is only useful when a super- tance is high for hospital-acquired MRSA in some areas. This ficial wound is first developing infection. Because of the is a concern in patients with diabetes who are often exposed lack of robust evidence of efficacy and concern for adverse to the health care system. In a recent study of treatment for events, high cost, and drug resistance, use of topical antimi- community-acquired skin infections with a high MRSA rate crobials, including iodine and silver-based dressings, is not (e.g., , ), there was no difference between routinely recommended to decrease the bioburden of a dia- clindamycin and trimethoprim/sulfamethoxazole; however, betic foot wound or for the treatment of uninfected diabetic patients with diabetes were excluded (Miller 2015). foot wounds. Fluoroquinolones are not recommended as single agents for treatment of infections caused by S. aureus because of the Oral Therapy potential for resistance to develop during treatment. The FDA For mild and many moderate DFIs, oral antibiotics can be recently issued a warning against their use for minor infec- used. For some moderate DFIs and severe DFIs that ini- tions because of concern over serious adverse events that tially require parenteral therapy, oral therapy can be used as can occur with this class (FDA 2016). a step-down once the patient is stable and infection is not progressing. Oral antibiotics with high bioavailability and equivalent intravenous-to-oral conversions are desirable for Although many patients with moderate and even severe DFIs deep-seated DFIs and DFO. Although some oral β-lactams may be de-escalated from intravenous to oral antibiotics, such as amoxicillin and cephalexin have fairly high bioavail- others (especially those with DFO) will require intravenous ability, they lack equivalent intravenous-to-oral conversions. antibiotics for the entire therapy. Most of these patients will For example, in a patient with normal renal function, be stable enough to receive this treatment outside the hos- may be dosed at 1–2 g intravenously every 8 hours; however, pital; this is known as outpatient parenteral antimicrobial oral cephalexin is usually dosed at 500 mg every 6 hours therapy (OPAT). The IDSA has published guidelines on the

ACSAP 2016 Book 3 • Infection Primary Care 13 Diabetic Foot Infections proper treatment of OPAT patients (Tice 2004). No single drug is no good evidence to continue antibiotic therapy until the or combination of agents appears to be superior to others for wound is fully healed; this will be an extended period for many OPAT; treatment should be tailored to culture results and the patients because of poor would healing properties. Table 1-4 most probable pathogens. lists the recommended duration of antibiotic therapy for DFIs Tigecycline, which did not meet the noninferiority criteria (without involvement of bone). compared with ertapenem in patients with DFIs, including some with osteomyelitis, is not generally recommended. In Wound Care this phase III, randomized, double-blind, multicenter trial, the Patients with diabetic foot wounds should receive appropri- safety and efficacy of tigecycline 150 mg intravenously daily ate wound care to ensure optimal healing. Antibiotic therapy and ertapenem 1 g intravenously daily were compared with for infected wounds may be insufficient unless combined with or without vancomycin in patients with DFIs with and with- appropriate wound care. To ensure proper healing, the wound out osteomyelitis. In the modified intention-to-treat analysis, must be well vascularized, free of debris and necrotic tissue, 71.4% of the patients who received tigecycline had clinical free of infection, and moist. Standard wound care includes cure compared with 77.9% in the ertapenem with or with- debridement, redistribution of pressure off the wound, and out vancomycin arm (95% CI for difference, -12.3 to -1.1). The moist wound dressings. noninferiority of tigecycline to ertapenem with or without Debridement vancomycin for clinical cure was determined using the lower Debridement of the wound removes debris, colonizing bacte- limit of a two-sided 95% CI. If the lower limit of the two-sided ria, necrotic and nonviable tissue, and any surrounding callus. 95% CI is not less than -10%, noninferiority is concluded. As In addition, it aids in granulation tissue formation, angio- a result, in this study, tigecycline did not meet the criteria for genesis, and promotion of the growth of new tissue, hence noninferiority and was therefore not approved for this indica- enabling wound healing. Sharp debridement with a scalpel, tion. and vomiting occurred significantly more often scissors, or tissue nippers is preferred. Other methods of in the tigecycline arm than in the ertapenem arm (39.8% vs. debridement include biological debridement with maggots 8.4% and 24.7% vs. 4.7%, respectively), resulting in signifi- and enzymatic debridement (e.g., with collagenase [Santyl]), cantly higher discontinuation rates in the tigecycline arm which is FDA approved for debriding chronic dermal ulcers (Lauf 2014). and severely burned areas. Studies with trimethoprim/sulfamethoxazole have shown

patterns of and increased ED visits when coad- Off-Loading Pressure ministered with sulfonylurea drugs, making this combination Redistributing pressure off the wound is an important compo- undesirable (Tan 2015; Parekh 2014). Table 1-3 lists the com- nent of appropriate wound care. The total contact cast device mon antibiotics used in DFIs, together with their spectrum of redistributes pressure to the entire weight-bearing surface to activity, dosing regimens, and adverse reactions. accelerate the healing of an ulcer.

Definitive Antimicrobial Therapy Wound Dressings Initial therapy for DFIs is empiric and guided by the clinical Because diabetic foot wounds are heterogeneous, no sin- presentation and the patient’s risk factors for multidrug- gle dressing is perfect; rather, a clinician should evaluate resistant organisms such as MRSA, Enterobacteriaceae individual wounds and choose the best dressing on a case- that produce extended-spectrum β-lactamase, and P. aeru- by-case basis. Creating a moist wound environment helps ginosa. Pathogen identification and susceptibilities may promote granulation, angiogenesis, and wound healing. take 3–5 days. Once these results are known, the antibiotic Types of dressings include continuously moistened saline spectrum should be narrowed to specifically target the iso- gauze for dry or necrotic wounds, hydrogels for dry and lated pathogens. This is critical because it can reduce cost, necrotic wounds to facilitate autolysis, occlusive and semi- reduce toxicity, minimize collateral damage (e.g., C. diffi- occlusive films for making dry wounds moist, alginates for cile diarrhea), and prevent the emergence of drug-resistant drying exudative wounds, hydrocolloids for absorbing exu- organisms. This is especially important for the carbape- dates and to facilitate autolysis, and foams for exudative nem and advanced-generation cephalosporin classes of wounds (Lipsky 2012). antibiotics because their broad-spectrum activity can eas- ily predispose patients to C. difficile infection. There is also Adjunctive Treatments increasing resistance to carbapenems in the United States Adjunctive treatments such as hyperbaric oxygen therapy and throughout the world. (HBOT), -derived growth factors, granulocyte col- ony-stimulating factor (G-CSF), and bioengineered skin Duration of Antimicrobial Therapy for DFIs equivalents lack robust evidence to support their routine use Duration of antimicrobial therapy should be based on severity in DFI treatment. These treatment modalities are expensive of infection, bone involvement, and clinical response. There and may not be feasible in a resource-limited setting.

ACSAP 2016 Book 3 • Infection Primary Care 14 Diabetic Foot Infections Table 1-3. Common Antibiotics Used for DFIs

Common Adverse Agent Antibacterial Activity Dosing Regimena Effects

Penicillins

Amoxicillin/ Gram-negative bacillib: 875 mg of amoxicillin GI upset, diarrhea clavulanate , Proteus sp., Klebsiella sp. PO q12hr or 500 mg of Gram-positive cocci: amoxicillin PO q8hr MSSA, , group A streptococci, 2 g ER PO q12hr may Anaerobes: Bacteroides sp., sp., be preferred for bone magna, Propionibacterium sp. infections

Ampicillin/ Gram-negative bacillib: 3 g IV q6hr GI upset, diarrhea, sulbactam E. coli, Proteus sp., Klebsiella sp., Gram-positive cocci: MSSA, Enterococcus faecalis, group A streptococci, viridans streptococci Anaerobes: Bacteroides sp., Peptostreptococcus sp., F. magna, Propionibacterium sp.

Dicloxacillin Gram-positive cocci: 500 mg PO q6hr Nausea MSSA, group A streptococci

Nafcillin Same as dicloxacillin 1–2 g IV q4–6hr Rash, diarrhea, nausea

Oxacillin Same as dicloxacillin 1–2 g IV q4–6hr Rash, diarrhea, nausea

Piperacillin/ Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 3.375 g IV q6hr or 4.5 g q8hr Rash, diarrhea tazobactam Serratia sp., Enterobacter sp., Citrobacter sp., P. aeruginosa, A. 4.5 g IV q6hr for baumannii osteomyelitis or Gram-positive cocci: Pseudomonas infection MSSA, group A streptococci, viridans streptococci, E. faecalis Anaerobes: Bacteroides sp., Peptostreptococcus sp., F. magna, Propionibacterium sp.

Cephalosporins

Cefazolin Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp. 2 g IV q8hr None significant Gram-positive cocci: MSSA, group A streptococci

Cefepime Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 1–2 g IV q8–12hr Neurologic, myoclonus, Serratia sp., Enterobacter sp., Citrobacter sp., P. aeruginosa C. difficile diarrhea Gram-positive cocci: MSSA, group A streptococci, viridans streptococci

Cefotetan Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp. 1–2 g IV q8–12hr C. difficile diarrhea, Gram-positive cocci: prolonged prothrombin MSSA, group A streptococci time Anaerobes: Bacteroides sp.,b Peptostreptococcus sp., F. magna, Propionibacterium sp.

Cefoxitin Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp. 1–2 g IV q6–8hr C. difficile diarrhea Gram-positive cocci: MSSA, group A Streptococcus Anaerobes: Bacteroides sp.,b Peptostreptococcus sp., F. magna, Propionibacterium sp.

(continued)

ACSAP 2016 Book 3 • Infection Primary Care 15 Diabetic Foot Infections Table 1-3. (Continued)

Ceftaroline Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 600 mg IV q12hr C. difficile diarrhea Serratia sp., Enterobacter sp., Citrobacter sp. Gram-positive cocci: MSSA, MRSA, group A streptococci, viridans streptococci Ceftazidime Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 1–2 g IV q8hr C. difficile diarrhea Serratia sp., Enterobacter sp., Citrobacter sp., P. aeruginosa Ceftriaxone Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 1–2 g IV q24hr C. difficile diarrhea Serratia sp., Enterobacter sp., Citrobacter sp. Gram-positive cocci: MSSA, group A streptococci, viridans streptococci Cephalexin Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp. 500 mg PO q6hr None significant Gram-positive cocci: MSSA, group A Streptococcus Carbapenems Doripenem Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 500 mg IV q8hr C. difficile diarrhea Serratia sp., Enterobacter sp., Citrobacter sp., P. aeruginosa, A. baumannii Gram-positive cocci: MSSA, group A streptococci, viridans streptococci Anaerobes: Bacteroides sp., Peptostreptococcus sp., F. magna, Propionibacterium sp. Ertapenem Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp., 1 g IV q24hr C. difficile diarrhea Serratia sp., Enterobacter sp., Citrobacter sp. Gram-positive cocci: MSSA, group A streptococci, viridans streptococci Anaerobes: Bacteroides sp., Peptostreptococcus sp., F. magna, Propionibacterium sp. Imipenem/ Same as doripenem 500 mg IV q6hr C. difficile diarrhea Cilastatin Meropenem Same as doripenem 1 g IV q8hr C. difficile diarrhea Gram-negative bacilli: E. coli, Proteus sp., Klebsiella 1–2 g IV q8hr None significant sp., Serratia sp., Enterobacter sp., Citrobacter sp., P. aeruginosa Lincosamides Clindamycin Gram-positive cocci: Oral: 300–450 mg q6hr, 600 C. difficile diarrhea, GI MSSA, MRSA, group A streptococci, viridans mg q8hr upset streptococci IV: 600–900 mg q8hr Anaerobes: Bacteroides sp.,b Peptostreptococcus sp., F. magna, Propionibacterium sp. Lipopeptides Daptomycin Gram-positive cocci: 4 mg/kg IV q24hr for skin Elevated creatinine MSSA, MRSA, Enterococcus sp., group A streptococci, and soft tissue infections, phosphokinase, viridans streptococci 6 mg/kg IV q24h for eosinophilic bacteremia or osteomyelitis, 8–10 mg/kg IV q24hr for severe MRSA infection refractory to vancomycin (continued)

ACSAP 2016 Book 3 • Infection Primary Care 16 Diabetic Foot Infections Table 1-3. (Continued)

Tetracyclines Doxycycline Gram-positive cocci: 100 mg IV/PO q12hr GI upset, photosensitivity MSSA, MRSA Minocycline Same as doxycycline 100 mg IV/PO q12hr GI upset, photosensitivity, dizziness Oxazolidinones Linezolid Gram-positive cocci: 600 mg IV/PO q12hr Myelosuppression, MSSA, MRSA, Enterococcus sp., group A streptococci, neuropathy, serotonin viridans streptococci syndrome Tedizolid Gram-positive cocci: 200 mg IV/PO q24hr Myelosuppression, MSSA, MRSA, Enterococcus sp., group A streptococci, neuropathy, serotonin viridans streptococci syndrome possible Vancomycin Gram-positive cocci: 15 mg/kg IV q12hr, goal Nephrotoxicity, red man MSSA, MRSA, Enterococcus sp., group A streptococci, trough concentration 10–20 syndrome viridans streptococci mcg/mL Dalbavancin Gram-positive cocci: Single-dose regimen: 1500 Infusion reactions MSSA, MRSA, Enterococcus sp., streptococci mg Two-dose regimen: 1000 mg IV on day 1, followed by 500 mg on day 8 Oritavancin Gram-positive cocci: 1200 mg IV single dose Infusion reactions MSSA, MRSA, Enterococcus sp., streptococci

Telavancin Gram-positive cocci: 10 mg/kg IV daily Infusion reactions, MSSA, MRSA, Enterococcus sp., streptococci QT prolongation, nephrotoxicity, foamy urine, dysgeusia Fluoroquinolones Ciprofloxacin Gram-negative bacillib: E. coli, Proteus sp., Klebsiella IV: 400 mg IV q8–12hr Tendinitis, tendon rupture, sp., Serratia sp., Enterobacter sp., Citrobacter sp., P. PO: 500–750 mg PO q12hr C. difficile diarrhea, QT aeruginosa prolongation, peripheral neuropathy Levofloxacin Gram-negative bacillib: E. coli, Proteus sp., Klebsiella 500–750 mg IV/PO q24hr Tendinitis, tendon sp., Serratia sp., Enterobacter sp., Citrobacter sp., rupture, C. difficile P. aeruginosa (with 750mg dose), diarrhea, QT prolongation, Gram-positive cocci: streptococci photosensitivity, peripheral neuropathy, CNS effects (with high doses) Moxifloxacin Gram-positive cocci: streptococci 400 mg IV/PO q24hr Tendinitis, tendon rupture, Gram-negative bacilli: E. coli, Proteus sp., Klebsiella sp. C. difficile diarrhea, Anaerobes: Bacteroides sp., QTc prolongation, Peptostreptococcus sp. photosensitivity, peripheral neuropathy, CNS effects Miscellaneous Metronidazole Anaerobes: Bacteroides sp., 500 mg IV/PO q8hr Metallic taste, nausea, Peptostreptococcus sp. neuropathy

(continued)

ACSAP 2016 Book 3 • Infection Primary Care 17 Diabetic Foot Infections Table 1-3. (Continued)

Tigecycline Gram-negative bacilli: E. coli, Klebsiella sp., Serratia sp., 100 mg IV × 1 load, followed Nausea, vomiting Enterobacter sp., Citrobacter sp. by 50 mg IV q12hr Gram-positive cocci: MSSA, MRSA, Enterococcus sp., group A streptococci, viridans streptococci Anaerobes: Bacteroides sp., Peptostreptococcus sp., F. magna, Propionibacterium sp.

Trimethoprim/ Gram-negative bacillib: PO: 1 double-strength tablet Rash, hyperkalemia sulfamethoxazole E. coli, Proteus sp., Klebsiella sp. q12hr or 20 mL (160 mg of Gram-positive cocci: TMP) q12hr MSSA, MRSA IVc: 3.5–4.0 mg TMP/kg/ dose IV q8–12hr

aDosages based on normal renal and hepatic function. bIncreasing resistance, consult local antibiograms. cLimited stability of parenteral admixture at room temperature; 5 mL TMP/125 mL D5W is stable for 6 hours. ER = extended release; IV = intravenously; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive S. aureus; PO = by mouth; q = every; TMP = trimethoprim.

with diabetes and chronic DFUs. Of the 103 patients available Table 1-4. Antibiotic Therapy Duration for DFIs for evaluation, the criteria for major amputation were met in 24% of patients (13 of 54) in the placebo group and 22% of Severity Duration patients (11 of 49) in the HBOT group (p=0.846). Healing of Mild 1–2 wk; 4 wk if slow to resolve the wound was not significantly different between the two Moderate 1–3 wk groups (20% in the HBOT group and 22% in the placebo group; p=0.823) (Fedorko 2016). Therefore, the use of HBOT cannot Severe 2–4 wk be routinely recommended for the healing of DFUs and DFIs.

DFI = diabetic foot infection. Platelet-Derived Growth Factors Information from: Lipsky BA, Berendt AR, Cornia PB, et al. Becaplermin is a platelet-derived growth factor gel prepa- 2012 Infectious Diseases Society of America clinical ration that has FDA-approved labeling for the treatment of practice guideline for the diagnosis and treatment of lower-extremity diabetic neuropathic ulcers that extend diabetic foot infections. Clin Infect Dis 2012;54:132-73. into the subcutaneous tissue or beyond and have an ade- quate blood supply. This agent improves wound healing by enhancing the formation of new granulation tissue, induc- Hyperbaric Oxygen Therapy ing fibroblast proliferation and differentiation, and promoting Hyperbaric oxygen therapy has been used as an adjunct to angiogenesis. Becaplermin has a boxed warning because in wound care to promote healing. It is designed to increase a postmarketing retrospective cohort study, patients treated oxygen delivery to ischemic tissue, hence promoting wound with three or more tubes of becaplermin had an increased rate healing and fighting infection. However, data for the use of of mortality secondary to malignancy (3.9 vs. 0.9 per 1000 HBOT in healing diabetic foot wounds are controversial. person-years) compared with controls. Efficacy of becapler- A longitudinal observational cohort study compared the min in wound healing from clinical trials has not translated effectiveness of HBOT with that of other conventional thera- into clinical practice (Wu 2007). Routine use of becaplermin pies administered in a wound care network for the treatment for DFUs cannot be recommended because its efficacy has of a DFU and prevention of lower-extremity amputation. The not consistently been demonstrated and because of its high authors studied 6259 patients with diabetes. Patients receiv- cost (average wholesale price of a 15-g tube of becaplermin ing HBOT were less likely to have healing of their foot ulcer is about $1100). (HR 0.68; 95% CI, 0.63–0.73) and more likely to have an ampu- tation (HR 2.37; 95% CI, 1.84–3.04) (Margolis 2013). Granulocyte Colony-Stimulating Factor A prospective, double-blind, randomized controlled clinical The few studies available of G-CSF (e.g., filgrastim, peg-fil- trial assessed the efficacy of HBOT in reducing the need for grastim) do not support the routine use of this therapy for major amputation and promoting wound healing in patients DFIs, although there may be some benefit. Adding G-CSF did

ACSAP 2016 Book 3 • Infection Primary Care 18 Diabetic Foot Infections Patient Care Scenario A 72-year-old man (weight 91 kg) has had a diabetic Appropriate wound care is given, cultures are obtained, foot ulcer for 15 months. He presents with a 3-day history and the patient is initiated on vancomycin intravenously, of right foot swelling, erythema, and pain, with a yellow ceftriaxone intravenously, and metronidazole intrave- foul-smelling purulent discharge from his ulcer. The ery- nously. The patient does not have osteomyelitis. After 5 thema is 3 cm around the ulcer. His medical history is days of therapy, cultures are finalized. The patient has also significant for type 2 diabetes (A1C 1 week ago was significant improvement because there is no drainage, 9.5%), hypertension, peripheral neuropathy, and periph- and the pain, erythema, and swelling are diminished. The eral vascular disease. The patient has no known drug physician wants to send the patient home and asks you for allergies and no systemic signs of infection. The physi- antibiotic recommendations. What antibiotic, route, and cian asks you to develop an antimicrobial regimen for him. duration would you recommend for this patient? MSSA

Drug Susceptibilities R Amoxicillin/ S clavulanate S Clindamycin R Linezolid S Vancomycin S Doxycycline S Trimethoprim/ S sulfamethoxazole

Drug Susceptibilities Ampicillin R Amoxicillin/clavulanate S Levofloxacin R Trimethoprim/ R sulfamethoxazole Cefoxitin S Ceftriaxone S

ANSWER This patient has had significant improvement after 5 days osteomyelitis and has had significant improvement after of intravenous therapy. According to the culture and sen- intravenous therapy. According to Table 1-5, 1–3 weeks of sitivities, it would be acceptable to de-escalate antibiotics antibiotics are recommended for moderate DFIs. Because to amoxicillin/clavulanate monotherapy. Amoxicillin/clavu- the duration of antibiotic therapy depends on clinical lanate will have activity against the patient’s MSSA. Oral response, 7–10 days of antibiotics (5 additional days of oral therapy is acceptable because the patient does not have amoxicillin/clavulanate) would be sufficient for this patient.

1. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:132-73 2. Bader MS. Diabetic foot infection. Am Fam Physician 2008;78:71-9.

not significantly affect the resolution of infection or wound was clinical cure, improvement, failure, and need for amputa- healing but was associated with a significant reduction in tion. There were no significant differences between the two lower-extremity amputation and length of hospital stay. In groups concerning the number of patients either cured or one study, 40 patients were randomized to receive conven- improved or the number of patients with therapeutic failure. tional treatment (antibiotic therapy plus local treatment) or However, the cumulative number of amputations observed conventional treatment plus G-CSF. The primary outcome after 9 weeks of treatment appeared to be lower in the

ACSAP 2016 Book 3 • Infection Primary Care 19 Diabetic Foot Infections conventional treatment plus G-CSF arm. Only three patients (n=50) had osteomyelitis. Of these 50 ulcers, 33 (66%) had a (15%) in this group required amputation compared with nine positive PTB test. Four of the 26 ulcers (15%) that did not have patients (45%) in the conventional treatment group (p=0.038) osteomyelitis had a positive PTB test. Therefore, the PTB test (de Lalla 2001). The IDSA guidelines do not recommend the had a sensitivity of 66% for osteomyelitis, specificity of 85%, routine use of G-CSF for the treatment of DFIs because robust positive predictive value of 89%, and negative predictive value evidence is lacking. of 56% (Grayson 1995).

Bioengineered Skin Equivalents Microbiology Human skin grafts and bioengineered skin substitutes (e.g., S. aureus is the most common pathogen isolated in DFO. Dermagraft, Apligraf, TheraSkin) have been studied in patients Despite being considered a contaminant in SSTIs, the second with noninfected, nonischemic chronic DFUs. In a systemic most common organism involved in DFO is Staphylococcus review and meta-analysis, five trials using skin grafts or sub- epidermidis. The most likely gram-negative bacilli to be cul- stitutes for DFU treatment met the inclusion criteria and were tured include E. coli, , Proteus sp., and included. The prespecified primary end point was complete P. aeruginosa. Isolation of obligate anaerobes in DFO is low; healing rate at the end of the trial. This meta-analysis favored the most common are Peptostreptococcus sp., F. magna, and the intervention group (bioengineered skin equivalents) com- Peptococcus sp. In a retrospective chart review of 80 patients pared with standard care (OR 1.46; 95% CI, 1.21–1.76) (Blozik with DFO who underwent a bone biopsy, 129 bacterial iso- 2008). Because of limited high-level evidence, the IDSA guide- lates were cultured, 54% of which were polymicrobial. The lines for DFIs do not recommend routine use of bioengineered most common organism was S. aureus (33% of all isolates). skin equivalents for DFUs. Gram-negative bacilli and anaerobes made up 20% and 4%, respectively, of the cultured microorganisms (Lesens 2011). DIABETIC FOOT OSTEOMYELITIS Diabetic foot osteomyelitis is present in up to 20% of mild Treatment to moderate infections and in 50%–60% of severely infected The clinical evidence base regarding treatment regimens for wounds. Diabetic foot osteomyelitis occurs because of the DFO is poor. Similar to DFIs, no data support the superiority contiguous spread of infection from a DFU with or without of one drug or combination of drugs, route, or therapy dura- direct trauma to the bone. The presence of DFO increases the tion. In a retrospective study of patients with DFO, the rate of likelihood of surgical interventions, including amputations. resolution of bone infection without was significantly higher when antibiotic therapy was directed by bone culture Diagnosis compared with empiric therapy (56.3% vs. 22.2%; p=0.04) The gold standard for diagnosing osteomyelitis combines (Senneville 2008). isolation of bacteria from a reliable sample of bone with histo- Antibiotic therapy selected for the treatment of DFO logic findings of osteonecrosis and . If obtaining should have good bone penetration. The antimicrobial should a bone sample is not feasible, the diagnosis of osteomyelitis ideally be active against stationary-phase bacteria as seen is made using a combination of clinical, radiographic, and lab- in attached to bone. Drugs that have activity against oratory findings. Diabetic foot osteomyelitis is suggested in stationary-phase bacteria include rifampin and fluoroqui- patients who have large (greater than 2 cm) or deep (greater nolones. Rifampin should never be used as monotherapy than 3 mm) foot ulcers, in patients when the bone is visible or because of the common occurrence of a single-step muta- palpable on a probe-to-bone (PTB) test, and in patients who tion, which confers resistance to the organism and renders have good blood supply to the affected foot and whose ulcer rifampin ineffective. In addition, if an oral antibiotic is chosen, does not heal despite at least 6 weeks of appropriate wound agents that have confirmed susceptibility and high oral bio- care and off-loading (Gemechu 2013; Lipsky 2012). availability should be used as previously mentioned for DFI. Magnetic resonance imaging can aid in the diagno- The initial empiric antibiotic choice for DFO should at least sis of DFO. It has high sensitivity and specificity and is the include activity against S. aureus. Fluoroquinolones are not most accurate imaging study for defining bone infection. recommended as single agents for S. aureus because of the In a patient with a DFU, the PTB test can be helpful in diag- high resistance rates that have developed to this class on nosing DFO. The PTB test involves probing for bone with a treatment and potential for selection of MRSA. sterile blunt wooden or metal tool. For an infected diabetic foot wound, a positive PTB test has a high positive predictive Therapy Duration value for osteomyelitis. However, a negative PTB test does Treatment duration for DFO depends on whether surgical not exclude osteomyelitis. One study assessed the relation- intervention is performed. If all of the infected tissue and ship between detection of bone using the PTB test and the bone has been removed (e.g., in a below-the-knee amputa- presence or absence of DFO that was defined clinically and/ tion), the recommended treatment duration is for only 2–5 or histopathologically. Of the 76 infected DFUs studied, 66% days postoperatively. If there is residual infected tissue, but

ACSAP 2016 Book 3 • Infection Primary Care 20 Diabetic Foot Infections not bone, treatment should be continued for 1–3 weeks. If Glycemic control, as recommended by the American Diabetes there is residual infected viable bone, treatment should be for Association (ADA); smoking cessation; blood pressure con- 4–6 weeks; practice guidelines recommend 8 weeks for treat- trol; and lipid management will help mitigate some of these ment of infections specifically caused by MRSA. If no surgery risk factors for DFIs. Glycemic control can be assessed using is performed or there is residual dead bone, at least 6 weeks A1C. According to the ADA, lowering the A1C to 7% or less of antibiotic therapy is recommended. helps reduce micro- and macrovascular complications of dia- In a prospective, multicenter, open-label, randomized betes. Therefore, for many patients, a reasonable A1C goal is study, 40 patients with DFO received either 6 or 12 weeks less than 7%. Pharmacists have a responsibility to counsel of antibiotics (treated nonsurgically). The primary outcome and educate patients with diabetes about their drugs, opti- was remission of osteomyelitis, which was defined as the mize , and combat polypharmacy. absence of any local or systemic sign of infection, stabilized Encouraging patients regarding medication adherence and or improved radiographic abnormalities on plain radiographs ownership of their diabetes management will help improve assessed at the end of treatment and 1 year later, and com- glycemic control. As a result, this will help reduce the inci- plete sustained healing of the wound. In addition, remission dence of DFUs and DFIs. was defined as no recurrence of infection or need for sur- gery during a posttreatment follow-up of at least 12 months. Foot Care Twelve patients in the 6-week group (60%) and 14 patients The ADA recommends that patients with diabetes perform a in the 12-week group (70%) achieved the primary outcome daily inspection of their feet for any red spots, blisters, cuts, (p=0.5). The authors concluded that a 6-week duration of and swelling. In addition, feet should be washed daily, and antibiotic therapy is sufficient in patients with DFO for whom interdigital spaces should be dried. Trimming of toenails is antibiotics alone are considered (Tone 2015). Table 1-5 sum- also recommended. Walking barefoot is not advised; hence, marizes the recommended treatment durations for DFO. the patient with diabetes should wear shoes and socks at all times. The ADA recommends an annual comprehensive PREVENTION foot examination by a health care provider. If the patient Diabetic foot ulcers and infection are a burden to the health has a history of foot problems, more frequent checks are care system, but they are avoidable. Preventing this morbid- recommended. ity and mortality involves optimal diabetes management and appropriate foot care. Practice Points Diabetes Management • About one in four patients with diabetes will have a signifi- As mentioned in Box 1-1, risk factors for DFIs include the pres- cant SSTI in their lifetime. These infections are preventable ence of peripheral vascular disease in the affecting limb, through diligent regular foot care and blood glucose control. poor glycemic control, and loss of protective sensation. • Risk factors for DFIs are presence of peripheral vascu- lar disease in the affected limb, poor glycemic control, neuropathy, traumatic foot wound, ulceration for more than 30 days, history of recurrent foot ulcers, previous lower- Table 1-5. Antibiotic Therapy Duration for DFO extremity amputation, and improper footwear. • Not all DFUs are infected. For clinically uninfected wounds, no antimicrobial therapy is required. Severity Duration • Empiric antimicrobial therapy for DFIs will be deter- No residual infected tissue 2–5 days mined by severity of infection and patient risk factors for after surgery multidrug-resistant organisms such as MRSA and P. aeru- ginosa. For mild infections, empiric therapy should target S. Residual infected tissue (not 1–3 wk aureus and group A Streptococcus. For moderate infections, bone) empiric therapy should target MRSA, enteric gram-negative bacilli (not P. aeruginosa), and anaerobes. For severe infec- Residual infected (but viable) 4–6 wk (8 wk for MRSA tions, empiric therapy should target MRSA, gram-negative bone infection) bacilli including P. aeruginosa, and anaerobes. • Mild-moderate DFIs can be treated with oral antibiotics. No surgery, or residual dead ≥ 6 wk • Pathogen identification and susceptibilities may take 3–5 days. Once these results are known, every attempt should bone be made to narrow the antibiotic spectrum. This is critical because it can reduce cost, avoid toxicity, minimize col- Information from: Lipsky BA, Berendt AR, Cornia PB, et al. lateral damage such as C. difficile diarrhea, and prevent the 2012 Infectious Diseases Society of America clinical prac- emergence of drug-resistant organisms. tice guideline for the diagnosis and treatment of diabetic • Good wound care and optimal diabetes management are foot infections. Clin Infect Dis 2012;54:132-73. essential for wound healing.

ACSAP 2016 Book 3 • Infection Primary Care 21 Diabetic Foot Infections REFERENCES Lipsky BA, Armstrong DG, Citron DM, et al. Ertapenem ver- Blozik E, Scherer M. Skin replacement therapies for dia- sus piperacillin/tazobactam for diabetic foot infections betic foot ulcers: systematic review and meta-analysis. (SIDESTEP): prospective, randomized, controlled, double- Diabetes Care 2008;31:693-4. blinded, multicenter trial. Lancet 2005;366:1695-703.

Centers for Disease Control. Diabetes Public Health Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic Resource 2014. Atlanta: Centers for Disease Control, 2015. antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double blinded, Centers for Disease Control. Diabetes Report Card 2014. multicenter trial of pexiganan cream. Clin Infect Dis Atlanta: Centers for Disease Control, 2015. 2008;47:1537-45.

Citron DM, Goldstein EJC, Merriam CV, et al. Bacteriology of Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious moderate to severe diabetic foot infections and in vitro activ- Diseases Society of America clinical practice guideline for ity of antimicrobial agents. J Clin Microbiol 2007;45:2819-28. the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:132-73. Corey GR, Good S, Jiang H, et al. Single dose oritavancin versus 7-10 days of vancomycin in the treatment of gram positive Margolis DJ, Gupta J, Hoffstad O, et al. Lack of effectiveness acute bacterial skin and skin structure infections: the SOLO II of hyperbaric oxygen therapy for the treatment of dia- noninferiority study. Clin Infect Dis 2015;60:254-62. betic foot ulcer and the prevention of amputation: a cohort study. Diabetes Care 2013;36:1961. de Lalla F, Pellizzer G, Strazzabosco M, et al. Randomized prospective controlled trial of recombinant granulocyte Miller LG, Daum RS, Creech B, et al. Clindamycin versus colony-stimulating factor as adjunctive therapy for limb trimethoprim-sulfamethoxazole for uncomplicated skin threatening diabetic foot infection. Antimicrob Agents infections. N Engl J Med 2015;372:1093-103. Chemother 2001;45:1094-8. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin- Dunne MW, Puttagunta S, Sprenger CR, et al. Extended- resistant S. aureus infections among patients in the duration dosing and distribution of dalbavancin into emergency department. N Engl J Med 2006;355:666-74. bone and articular tissue. Antimicrob Agents Chemother 2015;59:1849-55. Noel GJ, Bush K, Bagchi P, et al. A randomized, double blind trial comparing medocaril with vancomycin Fedorko L, Bowen JM, Jones W, et al. Hyperbaric oxygen plus ceftazidime for the treatment of patients with com- therapy does not reduce indications for amputation in plicated skin and skin structure infections. Clin Infect Dis patients with diabetes with nonhealing ulcers of the lower 2008;46:647-55. limb: a prospective, double-blind, randomized controlled . Diabetes Care 2016;39:392-9. Parekh TM, Raji M, Lin YL, et al. Hypoglycemia after anti- microbial drug prescription for older patients using FDA. Fluoroquinolone antibacterial drugs: Drug Safety sulfonylureas. JAMA Intern Med 2014;174:1605-12. Communication - FDA advises restricting fluoroquinolone Schaper NC, Andros G, Apelqvist J, et al. Diagnosis and treat- antibiotics. 05-12-2016. ment of peripheral arterial disease in diabetic patients Gemechu FW, Seemant F, Curley CA. Diabetic foot infections. with a foot ulcer. A progress report of the International Am Fam Physician 2013;88:177-84. Working Group on the Diabetic Foot. Diabetes Metab Res Rev 2012;28:218-24. Grayson ML, Gibbons GW, Balogh K, et al. Probing to bone in infected pedal ulcers. A clinical sign of underlying osteo- Senneville E, Lombart A, Beltrand E, et al. Outcome of dia- myelitis in diabetic patients. JAMA 1995;273:721. betic foot osteomyelitis treated nonsurgically. Diabetes Care 2008;31:637-42. Khanolkar MP, Bain SC, Stephens JW. The diabetic foot. Q J Med 2008;101:685-95. Solon EG, Dowell JA, Lee J, et al. Distribution of radioactivity in bone and related structures following administra- Lauf L, Ozsvar Z, Mitha I, et al. Phase 3 study comparing tion of [14C]dalbavancin to New Zealand white rabbits. tigecycline and ertapenem in patients with diabetic foot Antimicrob Agents Chemother 2007;51:3008-10. infections with and without osteomyelitis. Diagn Microbiol Infect Dis 2014;78:469-80. Tan A, Holmes HM, Kuo YF, et al. Coadministration of co- trimoxazole with sulfonylureas: hypoglycemia events Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors and pattern of use. J Gerontol A Biol Sci Med Sci for foot infections in individuals with diabetes. Diabetes 2015;70:247-54. Care 2006;29:1288-93. Tone A, Nguyen S, Devemy F, et al. Six week versus twelve Lesens O, Desbiez F, Vidal M, et al. Culture of per wound week antibiotic therapy for nonsurgically treated diabetic bone specimens: a simplified approach for the medical foot osteomyelitis: a multicenter open-label controlled management of diabetic foot osteomyelitis. Clin Microbiol randomized study. Diabetes Care 2015;38:302-7. Infect 2011;17:285-91. Wu SC, Driver VR, Wrobel JS, et al. Foot ulcers in the dia- Lipsky BA. Medical treatment of diabetic foot infections. Clin betic patient, prevention and treatment. Vasc Health Risk Infect Dis 2004;39:S104-14. Manag 2007;3:65-76.

ACSAP 2016 Book 3 • Infection Primary Care 22 Diabetic Foot Infections Self-Assessment Questions

Questions 1 and 2 pertain to the following case. 4. D.B. undergoes surgical debridement. A Gram stain A.B. is a 55-year-old man (height 78 inches, weight 46 kg) who shows many PMNs, gram-positive cocci in clusters, and presents with a 3-day history of right foot swelling and purulent gram-negative bacilli. After 5 days of intravenous ther- discharge from a 1-cm ulcer at the base of his foot. The ery- apy with vancomycin plus piperacillin/tazobactam, he thema around the ulcer is 0.7 cm. A.B. has a medical history is clinically improved and ready to be discharged to his of type 2 diabetes, hypertension, osteoarthritis, and peripheral primary care provider. Final wound cultures grew MRSA vascular disease but no known drug allergies. He was hospital- and E.coli. The MRSA is susceptible to daptomycin, line- ized 3 months ago for total knee arthroplasty but has completed zolid, , and vancomycin and resistant to physical therapy and says he is “walking good now.” Vital signs erythromycin, clindamycin, levofloxacin, oxacillin, and and laboratory values include temperature 37.3°C, heart rate 86 trimethoprim/sulfamethoxazole. E.coli is an ESBL pro- beats/minute, respiratory rate 23 breaths/minute, blood pres- ducer and is only susceptible to amikacin, gentamicin, sure 153/92 mm Hg, glucose 151 mg/dL, WBC 11 × 103 cells/ meropenem, and piperacillin-tazobactam. It is resistant mm3, erythrocyte sedimentation rate 110 mm/hour, and A1C 6%. to ampicillin-sulbactam, all , fluoroquino- lones, tobramycin and trimethoprim/sulfamethoxazole. 1. Which one of the following risk factors places A.B. at D.B. has Medicare Part A, which pays for intravenous greatest risk of DFIs? antibiotics administered in an infusion unit if needed. He A. Type 2 diabetes has transportation for only one trip to the clinic each day. B. Osteoarthritis Which one of the following is best to recommend for D.B.? C. Hypertension A. Daptomycin 400 mg intravenous daily and D. Peripheral vascular disease ceftriaxone 2 g intravenously daily 2. Which one of the following is best to recommend as an B. Vancomycin 1.5 g intravenously daily and ertapenem empiric regimen for A.B.? 1 g intravenously daily A. Cephalexin orally 500 mg every 6 hours plus C. Linezolid 600 mg orally once daily and gentamicin doxycycline orally 100 mg twice daily × 1 week intravenously 1.5 mg/kg every 12 hours B. Ciprofloxacin orally 750 mg twice daily plus D. Doxycycline 100 mg orally twice daily and amoxicillin orally 500 mg every 8 hours × 2 weeks moxifloxacin 400 mg orally once daily C. Amoxicillin/clavulanate 875 mg orally twice daily × 1 5. Which one of the following treatment durations is best to week recommend for D.B.? D. Vancomycin intravenously 15 mg/kg × 1 week A. 10 days B. 3 weeks Questions 3–5 pertain to the following case. C. 6 weeks D.B. is an 82-year-old m an (weight 101 kg) with a history of D. 3 months type 2 diabetes, peripheral vascular disease, neuropathy, 6. A prospective randomized controlled trial examined depression, chronic disease, and gout. He presents to amputation rates after mild DFIs caused by MRSA the ED with confusion and a temperature of 38.6°C (101.5°F). were treated with either trimethoprim/sulfamethoxa- D.B. stepped on a grandchild’s toy about 2 months ago and zole or clindamycin. Amputation rates at day 30 were subsequently developed a 3.5-cm halo of erythema around 4% for trimethoprim/sulfamethoxazole (n=45) and 4.5% the wound on the bottom his left foot. The wound is puru- for clindamycin (n=44) (p=0.97, 95% CI, 0.5 [-1.4 to 1.8]). lent with malodorous drainage. D.B.’s WBC count is 12.3 × 103 Which one of the following best describes the number cells/mm3 and SCr is 1.6 mg/dL. He is admitted to the hospital needed to treat with trimethoprim/sulfamethoxazole to for further treatment with intravenous antibiotics. An MRI of prevent one amputation compared with clindamycin? his foot reveals diffuse swelling of the subcutaneous tissue A. 100 but no inflammation of bone. D.B. is hemodynamically stable. B. 200 3. Which one of the following best classifies D.B.’s diabetic C. 50 foot infection (DFI)? D. Not applicable A. Mild 7. A 51-year-old man with diabetes presents to the clinic B. Moderate with a left foot abscess. The abscess is drained, and cul- C. Severe tures show gram-positive cocci in clusters. The patient D. Severe with osteomyelitis states that he would prefer not to take daily infusions

ACSAP 2016 Book 3 • Infection Primary Care 23 Diabetic Foot Infections because of his work schedule. Which one of the following normal limits. His home drugs include glargine, is the best antimicrobial regimen to recommend for this insulin aspart, citalopram, albuterol, ipratropium, furose- patient? mide, benazepril, and metoprolol succinate. Which one of the following is the best antimicrobial therapy to rec- A. Oritavancin ommend for this patient’s DFI? B. Tigecycline C. Telavancin A. Levofloxacin 750 mg orally daily D. Dalbavancin B. Cephalexin 500 mg orally three times daily C. Clindamycin 600 mg orally three times daily Questions 8–10 pertain to the following case. D. Linezolid 600 mg orally twice daily D.F. is a 67-year-old woman who presents to the clinic with 12. A 45-year-old man with and gastroesoph- complaints of a sore and slightly swollen foot. She checks her ageal reflux disease (GERD) steps on a nail while working feet daily, and 4 days ago, she noticed a stone in her shoe. On on the family farm. His laboratory results are as follows: inspection today, she has a 1-cm halo of erythema around the WBC 14 × 103 cells/mm3, SCr 0.8 mg/dL, erythrocyte sedi- ulcer on the bottom of her right foot. It is indurated and red mentation rate 65 mm/hour, and CRP 1.5 mg/L. An MRI but not weeping. D.F. is embarrassed by the state of her long reveals acute changes in the bottom of his calcaneus nails, saying, “I don’t visit a salon or anything fancy like that bone consistent with osteomyelitis. The patient receives for pedicures.” Her temperature is 37.4°C (99.3°F) and she is broad-spectrum antibiotics and a booster with the in no apparent distress. D.F. takes metformin and glipizide for tetanus, diphtheria, and acellular pertussis vaccine. The diabetes, lisinopril for hypertension, and aspirin for cardio- next day, surgical debridement occurs, and a deep tissue vascular risk reduction. She has otherwise been healthy for specimen is sent to the laboratory. The Gram stain shows the past year; her A1C is 6.8%. many PMNs and gram-positive cocci in clusters. The 8. Which one of the following best classifies D.F.’s diabetic patient has a history of allergic reaction to penicillin (ana- foot ulcer (DFU)? phylaxis). He takes insulin for his diabetes and A. Uninfected for GERD. After 1 week of taking vancomycin the patient B. Mild is clinically improving, but his SCr concentration rises to C. Moderate 1.8 mg/dL with an elevated vancomycin trough of 28 mcg/ D. Severe mL. The physician decides to change the regimen to dap- tomycin. Which one of the following daptomycin dosing 9. Which one of the following is best to recommend for regimens is best to recommend for outpatient parenteral treatment of D.F.’s DFU? antimicrobial therapy in this patient? A. Local wound care A. 4 mg/kg daily B. Trimethoprim/sulfamethoxazole 800/160 mg orally B. 6 mg/kg daily twice daily C. 8 mg/kg daily C. Ciprofloxacin 500 mg orally twice daily D. 10 mg/kg daily D. Cephalexin 500 mg orally four times daily 13. An 89-year-old woman presents with a medical history 10. During a follow-up visit, D.F. would like to know what she of atrial fibrillation, type 2 diabetes, osteoarthritis, and might do to prevent future infections like this. Which one general anxiety disorder. Her home drugs include amiod- of the following education points is best for D.F.? arone, warfarin, metformin, fluoxetine, calcium carbonate A. Inspect feet weekly with vitamin D, as-needed acetaminophen, and a multi- B. Wash feet daily, dry interdigital spaces, and trim vitamin. The patient is in clinic with a DFI. She has been toenails treated for the last week with amoxicillin-clavulanate. C. Improve glycemic control Cultures are now growing MRSA and E. coli. The patient’s D. Wear socks with her shoes MRSA is susceptible to clindamycin, trimethoprim/sul- 11. An 81-year-old man has a medical history of type 2 dia- famethoxazole, and linezolid while being resistant to betes, depression, chronic bronchitis, and heart failure. tetracycline. Her E. coli is resistant to amoxicillin/clavu- He has had several hospital admissions in the past year lanate, tetracycline, and trimethoprim/sulfamethoxazole, for chronic obstructive pulmonary disease exacerba- but it is susceptible to cephalexin and levofloxacin. The tions, including a 4-day hospital stay just 2 weeks ago. patient’s next appointment at anticoagulation clinic is in Today, he presents with cellulitis of the left foot sur- 2 weeks. Her QTc was 501 milliseconds the last time it rounding the chronic ulcer on the heel. The erythema was checked. The physician would like to start her on oral around the ulcer is 0.5 cm. The probe-to-bone (PTB) test antibiotics. Which one of the following is best to recom- is negative, and his vital signs and blood tests are within mend for this patient?

ACSAP 2016 Book 3 • Infection Primary Care 24 Diabetic Foot Infections A. Doxycycline 100 mg orally once daily plus undergoes wound debridement but not amputation; there- levofloxacin 500 mg orally daily fore, the residual infected bone remains. Bone samples were B. Trimethoprim/sulfamethoxazole 1 double-strength taken during surgery and sent for cultures. The following tablet orally twice daily organisms and susceptibilities were obtained: C. Clindamycin 450 mg orally four times daily plus cephalexin 500 mg orally four times daily Staphylococcus epidermidis D. Linezolid 600 mg orally twice daily plus levofloxacin Drug Susceptibilities 750 mg orally daily Clindamycin R

Question 14 and 15 pertain to the following case. Daptomycin S D.L. is a 45-year-old man with diabetes who presents with Doxycycline R purulent drainage from his left heel for 4 days. He states he hit Linezolid S his foot on a rock while swimming in a lake. He self-medicated Oxacillin R with topical triple antibiotic ointment, with no improvement in symptoms. D.L. reports chills, fevers, left foot swelling, and Rifampin S pain on touch. His WBC is 14 × 103 cells/mm3, temperature Trimethoprim/ R 100°F, SCr 1.0 mg/dL, and erythrocyte sedimentation rate 12 Sulfamethoxazole mm/hour. The physician wants to rule out osteomyelitis, then Vancomycin S treat for common foot and water pathogens. 14. Which one of the following would best assist in determin- ing whether D.L. has osteomyelitis? Drug Susceptibilities A. MRI of left foot Ampicillin R B. PTB test Amoxicillin/clavulanate S C. Radiography of left foot Cefazolin R D. Wound greater than 5 cm Cefoxitin R 15. Nothing is identified on D.L.’s Gram stain or culture, and osteomyelitis is ruled out. Which one of the following is Ceftriaxone S the best antimicrobial regimen to recommend for D.L.? Ertapenem S A. Moxifloxacin 400 mg orally daily Gentamicin S B. Amoxicillin/clavulanate 875 mg orally twice daily Levofloxacin R C. Linezolid 600 mg orally twice daily plus Trimethoprim/ R ciprofloxacin 750 mg orally twice daily Sulfamethoxazole D. Vancomycin (goal trough 15–20 mcg/mL) plus gentamicin 5 mg/kg every 8 hours 17. Which one of the following is best to recommend for 16. A study will compare outcomes in patients with mild DFIs. T.D.? Patients will be randomized to receive either clindamycin A. Ertapenem intravenously 1 g every 24 hours for 4 or linezolid for 2 weeks. The investigators want to enroll weeks 100 patients in each group. The primary end point is the B. Linezolid 600 mg orally twice daily plus ceftriaxone proportion of patients who have a clinical cure at the end intravenously 2 g every 24 hours for 10 weeks of 2 weeks. Which one of the following is the best statis- C. Vancomycin intravenously (goal trough 15–20 mcg/ tical test for this type of investigation? mL) plus ceftriaxone intravenously 2 g every 24 A. Chi-square test hours for 6 weeks B. Paired t-test D. Daptomycin intravenously 6 mg/kg every 24 hours C. Student t-test plus amoxicillin/clavulanate 875 mg orally twice D. Analysis of variance daily for 2 weeks

Questions 17 and 18 pertain to the following case. 18. After appropriate therapy is selected, T.D.’s wound is slow T.D., an 81-year-old man with diabetes, received a new diag- to heal. The physician would like to know more about nosis of right foot osteomyelitis after he developed a chronic adjunctive therapy that can help prevent amputation. nonhealing wound ulcer on his right great toe 5 weeks ago. Although not recommended for routine use, which one of He had taken cephalexin for 2 weeks before admission. T.D. the following therapies would be most appropriate for T.D.?

ACSAP 2016 Book 3 • Infection Primary Care 25 Diabetic Foot Infections A. Granulocyte colony-stimulating factor A. Cephalexin 500 mg orally four times daily B. Hyperbaric oxygen therapy B. Amoxicillin 875 mg orally twice daily C. Bioengineered skin equivalent C. Doxycycline 100 mg orally twice daily D. Platelet-derived growth factor D. Trimethoprim/sulfamethoxazole 1 double-strength tablet orally twice daily Questions 19 and 20 pertain to the following case. 20. Which one of the following is best to recommend as the T.Z. is an 88-year-old man with a long-standing history of vas- therapy duration for T.Z.’s DFI? cular insufficiency, diabetes mellitus (A1C 9%), hypertension, A. 7 days and obesity. He presents to the ED with erythema and warmth B. 21 days and swelling of his left heel for about 4 days. On examination, C. 28 days there is a 1-cm halo of erythema around the heel ulcer. T.Z. D. 42 days has no fever or leukocytosis. 19. Which one of the following is best to recommend for T.Z.’s DFI?

ACSAP 2016 Book 3 • Infection Primary Care 26 Diabetic Foot Infections